Amides and Anilides

An ab initio study of N- vs O-protonation using formamide (108), the somewhat strained A-formylazetidine (109), highly strained AMormylaziridine (110), and various 

The alkaline hydrolysis of the compounds (118)-(123) in 70% (v/v) dioxane-water at various temperatures has been investigated.101 Intramolecular catalysis by the neighbouring carbonyl group occurs in the alkaline hydrolysis of (118)—(121) and the alkaline hydrolysis of (122) and (123) is rapid owing to their lactone structures. The hydrolyses of C-terminal amides of a-amino acids was dealt with earlier.56 Also, the acid-catalysed cleavage of /V-(2-aminophenyl)phthalamic acid (82) was discussed earlier.72 

Two mechanisms (i.e. direct hydrolysis and alternatively a path via an unstable acyl phosphate intermediate) are involved in the hydrolysis in phosphate buffer of N-arylsulfonyl /1-lactams such as (130).107 The acyl phosphate intermediate can be trapped with hydrazine. The alkaline hydrolysis of some torsionally distorted lactams, i.e. the bridged bcnz[c/t ]isoquinolin-l-ones (131), in 70% (v/v) DMSO-water has been compared under the same conditions with the hydrolysis of A/iV-dimethyl-1 -naphthamide (132). The relative rates of reaction and activation parameters indicate the effect of torsional distortion.108 The reaction of the tricyclic azetidinones (133) with trifluoroacetic acid gives the bicyclic thioesters (135). The mechanism may involve acid-catalysed elimination of methanethiol to give an azetinone intermediate (134) which, after nucleophilic attack of the thiol, is converted into (135).109 

The degradation of several commercial penicillin antibiotics has been reported.110-113 Thus the kinetics and mechanism of decomposition of cefazolin ester (136) in phosphate buffers110 and the effect of hexadecyltrimethylammonium bromide-based microemulsions on the decomposition of the antibiotic cephalosporin, cephaclor (137)111 have been reported. Reaction of the latter can occur intramolecularly or intermolecularly by hydroxide attack. Degradation in the solid state of cephaclor (137) has also been reported.112 The same group has looked at the decomposition under aqueous acidic conditions.113 The degradation pathways that have been recognized are 

The neutral and acid-catalysed mechanisms of hydrolysis of formamide, HCONH2, have been revisited and a comparison made between ab initio, semiempirical and DFT results Ab initio MO calculations on the alkaline hydrolysis of para-substituted acetanilides (135) in the gas phase have shown that the activation energy depends on the nature of electron-withdrawing groups (e.g. X = NO2, CN, Cl) but is invariant for electron-donating groups (X = NH2, OMe).  

Theoretical calculations of minimum energy structures and thermodynamic terms using SCF theory with thermodynamic and solvation corrections have been made of the cyclization of l-amino-8-(acetylamino)naphthalene (136) to give 2-methylperimidine 

Alkaline earth (Ba, Sr) metal ethoxides have been found to be more reactive than free ethoxide in the ethanolysis of simple activated amides such as A-methyl-2,2,2-trifluoroacetanilide (140), A-methyl-1-chloroacetanilide (141) and m-nitro-A-methyl-2,2,2-trifluoroacetanilide (142) enhanced catalysis was observed upon addition of equimolar amounts of 18-crown-6.  

2-(4-Nitrobenzoylamino)-2,2-dimethylpropanamide (143 R = Me) reacts in methanol-DMSO solution with sodium methoxide to yield 5,5-dimethyl-2-(4-nitrophenyl)imidazol-4(5//)-one (144 R = Me). The 4-methoxyphenyl derivative and the parent phenyl derivative react similarly, as do compounds in which variation of the 2-substitutent (R = Pr , Ph, 4-O2NC6H4) was made. The mechanism of the cyclization probably involves initial formation of the anion of the alkanamide (145), which adds to the carbonyl group of the benzamido moiety to yield the tetrahedral oxyanion (146) proton transfer and dehydration then yield the heterocycle (144). The kinetics of hydrolysis in water at 70 °C and pH 2-11 of A-glycidylmorpholine (147) have been reported.  

An ab initio study of the acid hydrolysis of /3-lactams has yielded a value of 14.23 kcal moU for the energy barrier for the opening of the ring. Two theoretical studies of N-methyl-2-azetidinone (149) have been reported. In the first, semiempirical calculations 

Continued synthetic work in the general area of anesthetic null lies revealed the interesting fact that the amide function can III reversed. That is, compounds were at least equally effective 111 which the amide nitrogen was attached to the aromatic ring iiiiil the carbonyl group was part of the side chain. 

Acylation of ortho-toluidine with 2-bromopropionyl bromide Ifords the haloamide (73). Displacement of the halogen by ii uns of butylamine affords prilocaine (74).  

Replacement of one of the aromatic methyl groups in lido- M/ne by a carboxylic ester proves consistent with pharmacologic lu-Livity. The product, tolycaine (76) is obtained from the iiiithranilic ester, 75, by the same two-step scheme as the proto-Iypc drug. 

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Enantioselective reactions of laterally lithiated amides and anilides have been reported by Beak and coworkers but these are properly asymmetric transformations in which stereoselectivity arises subsequent to the lateral lithiation step they are not enantioselective lithiations. 

From Acid Amides and Anilides.—In the aliphatic series the cyanides are formed from the acid amides by loss of water, the amides themselves resulting from the ammonium salts by a similar loss of water. 

Two bonding mechanisms have also been proposed for the stereochemical resolution of enantiomeric amides and anilides on a type I CSP based on (J )-N-(3,5-dinitroben2oyl) phenyl glycine (15-18). Both the mechanisms are based on dipole-dipole interactions between the solute and CSP. The difference arises from the positioriing of the solutes relative to the CSP vrithin the solute/CSP complexes. Pirkle and McCune (15) labeled the two possibilities "head to head" and "head to tail" dipole stacking. 

N-Alkylcurboxylic acid amides and anilides are dealkylated in good yield when heated with an excess of the reagent at 19()-20()°."... 

Many different types of nitrogen-containing compounds have been shown in oil shale. Poulson and co-workers reported that pyridines and pyrroles were major types of nitrogen compounds in shale oil. Cyclic amides and anilides were proposed as possible additional types of nitrogen compounds in shale oil. Van Meter and co-workers found benzonitriles in shale oil naphtha. Brown and co-workers identified alkylpyr-idines, cycloalkanopyridines, alkylanilines, quinolines, tetrahydroquinolines, and tetrahydroisoquinolines in... 

That proteolytic enzymes can indeed catalyze the reversal of proteolysis was shown by Bergmann and Fraenkel-Conrat in 1937 in their study of the synthesis of insoluble amides and anilides catalyzed by papain and bromelin. These studies have been extended recently by other investigators. 113,114 q hg enzymes displayed the same specificity in synthesis as they did in hydrolysis. Moreover, when the free energy of the reaction was lowered by the subseqeunt hydrolysis of the product rather than by precipitation, the synthetic reaction also occurred but the net result of the reaction was a hydrolysis. These experiments serve only as models since in vivo such insoluble products as the anilides are not formed nor would protein synthesis result in net hydrolysis. 

A learning set of 1663 structurally diverse compounds was built. It contained 28 aliphatic hydrocarbons 52 aromatic hydrocarbons 74 alcohols, ethers, or phenols 27 aldehydes and ketones 42 acids and esters 66 amines and nitriles 23 amides and anilides 9 sulfur-containing hydrocarbons 18 nitro arenes 10 amino acids 54 halogenated hydrocarbons 35 nucleosides 25 nucleoside bases and 1200 multifunctional compounds. 

Amides and anilides Benzoylprop-ethyl, difenamide, naptalam, pronamide, propanil... 

Already mentioned have been labeling of aromatic (and some heteroaromatic) rings ortho to carbonyl-based functions such as ketones, esters, amides and anilides, and heteroaromatic functions such as 2-pyridyl and the fused analog benzoquinoline. Modest extensions of the range of carbonyl-based functions to tritiation of ureas have been reported , including 124... 

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